tbuckley/cabot-search huggingface dataset:
Protection against severe COVID-19 after second booster dose of adapted bivalent (original/Omicron BA.4-5) mRNA vaccine in persons ≥ 60 years, by time since infection, Italy, 12 September to 11 December 2022
Authors: Massimo Fabiani, Alberto Mateo-Urdiales, Chiara Sacco, Emmanouil Alexandros Fotakis, Maria Cristina Rota, Daniele Petrone, Marco Bressi, Martina Del Manso, Andrea Siddu, Giorgio Fedele, Paola Stefanelli, Antonino Bella, Flavia Riccardo, Anna Teresa Palamara, Giovanni Rezza, Silvio Brusaferro, Patrizio Pezzotti
Journal: Eurosurveillance (2023)

Effectiveness against severe COVID-19 of a second booster dose of the bivalent (original/BA.4-5) mRNA vaccine 7-90 days post-administration, relative to a first booster dose of an mRNA vaccine received ≥ 120 days earlier, was ca 60% both in persons ≥ 60 years never infected and in those infected > 6 months before. Relative effectiveness in those infected 4-6 months earlier indicated no significant additional protection (10%; 95% CI: -44 to 44). A second booster vaccination 6 months after the latest infection may be warranted.
Author Correction: Toxic expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD
Authors: Lindsey D. Goodman, Mercedes Prudencio, Nicholas J. Kramer, Luis F. Martinez-Ramirez, Ananth R. Srinivasan, Matthews Lan, Michael J. Parisi, Yongqing Zhu, Jeannie Chew, Casey N. Cook, Amit Berson, Aaron D. Gitler, Leonard Petrucelli, Nancy M. Bonini
Journal: Nature Neuroscience (2023)
The Global Economic Cost of Cancer—Estimating It Is Just the First Step!
Authors: Gilberto Lopes
Journal: JAMA Oncology (2023)

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Improving Clinician Well-being and Patient Safety Through Human-Centered Design
Authors: Lauren E. Benishek, Allen Kachalia, Lee Daugherty Biddison
Journal: JAMA (2023)

This Viewpoint discusses the need for clinicians to be involved in every stage of the development of patient safety interventions in order to not only improve patient care, but also maximize the interventions’ effectiveness and ensure clinician well-being and buy-in.
Predicting Risk of Cardiotoxic Effects in Breast Cancer: Are We There Yet?
Authors: Tauben Averbuch, Mamas A. Mamas, Harriette G. C. Van Spall
Journal: JAMA Network Open (2023)

Elisé G. Kaboré, MD; Conor Macdonald, PhD; Ahmed Kaboré, PhD; Romain Didier, MD; Patrick Arveux, MD, PhD; Nicolas Meda, MD, PhD; Marie-Christine Boutron-Ruault, MD, PhD; Charles Guenancia, MD, PhD
RELA tunes innate-like interferon I/III responses in human T cells
Authors: Nadia Jeremiah, Hermine Ferran, Konstantina Antoniadou, Kevin De Azevedo, Jovan Nikolic, Mathieu Maurin, Philippe Benaroch, Nicolas Manel
Journal: The Journal of Experimental Medicine (2023)

In innate immune cells, intracellular sensors such as cGAS-STING stimulate type I/III interferon (IFN) expression, which promotes antiviral defense and immune activation. However, how IFN-I/III expression is controlled in adaptive cells is poorly understood. Here, we identify a transcriptional rheostat orchestrated by RELA that confers human T cells with innate-like abilities to produce IFN-I/III. Despite intact cGAS-STING signaling, IFN-I/III responses are stunted in CD4+ T cells compared with dendritic cells or macrophages. We find that lysine residues in RELA tune the IFN-I/III response at baseline and in response to STING stimulation in CD4+ T cells. This response requires positive feedback driven by cGAS and IRF7 expression. By combining RELA with IRF3 and DNA demethylation, IFN-I/III production in CD4+ T cells reaches levels observed in dendritic cells. IFN-I/III production provides self-protection of CD4+ T cells against HIV infection and enhances the elimination of tumor cells by CAR T cells. Therefore, innate-like functions can be tuned and leveraged in human T cells.
Influenza A(H5N1) detection in two asymptomatic poultry farm workers in Spain, September to October 2022: suspected environmental contamination
Authors: Esteban Aznar, Inmaculada Casas, Alejandro González Praetorius, María José Ruano Ramos, Francisco Pozo, María José Sierra Moros, María Victoria García Rivera, Azucena Sánchez Sánchez, Elena García Villacieros, Gabriela Saravia, María Iglesias-Caballero, Elena Román Marcos, Lucía García San Miguel
Journal: Eurosurveillance (2023)

In autumn 2022, the Spanish Influenza National Reference Laboratory (NRL) confirmed the detection of influenza A(H5N1) in samples from two asymptomatic workers linked to an outbreak in a poultry farm in Spain. Nasopharyngeal swabs were taken according to a national screening protocol for exposed workers. Absence of symptoms, low viral load and negative serology in both workers suggested environmental contamination. These findings motivated an update of the early detection strategy specifying timing and sampling conditions in asymptomatic exposed persons.
Detection of the Omicron BA.1 Variant of SARS-CoV-2 in Wastewater From a Las Vegas Tourist Area
Authors: Van Vo, Richard L. Tillett, Katerina Papp, Ching-Lan Chang, Anthony Harrington, Michael Moshi, Edwin C. Oh, Daniel Gerrity
Journal: JAMA Network Open (2023)

Importance Interpretation of wastewater surveillance data is potentially confounded in communities with mobile populations, so it is important to account for this issue when conducting wastewater-based epidemiology (WBE). Objectives To leverage spatial and temporal differences in wastewater whole-genome sequencing (WGS) data to quantify relative SARS-CoV-2 contributions from visitors to southern Nevada. Design, Setting, and Participants This cross-sectional wastewater surveillance study was performed during the COVID-19 pandemic (March 2020 to February 2022) and included weekly influent wastewater samples that were analyzed by reverse transcription–quantitative polymerase chain reaction to quantify SARS-CoV-2 RNA and WGS for identification of variants of concern. This study was conducted in the Las Vegas, Nevada, metropolitan area, which is a semi-urban area with approximately 2.3 million residents and nearly 1 million weekly visitors. Samples were collected from 7 wastewater treatment plant (WWTP) locations that collectively serve the vast majority of southern Nevada (excluding the small number of septic systems) and 1 manhole serving the southern portion of the Las Vegas Strip. With Las Vegas tourism returning to prepandemic levels in 2021, it was hypothesized that visitors were contributing a disproportionate fraction of SARS-CoV-2 RNA to the largest WWTP in southern Nevada, potentially confounding efforts to estimate COVID-19 incidence in the local community through WBE. Main Outcomes and Measures Relative SARS-CoV-2 load and variants from visitors vs the local population. Results The Omicron BA.1 VOC was detected in the Las Vegas Strip manhole approximately 1 week before its detection at the WWTP locations (December 13, 2021) and by clinical testing (December 14, 2021). On December 13, Omicron-specific mutations represented a mean (SD) of 48.0% (4.2%) of all genomes from the Las Vegas Strip manhole and 4.1% (1.4%) of all genomes at facilities 2 and 3; by December 20, Omicron-specific mutations represented means (SD) of 82.0% (3.0%) of all genomes at the Las Vegas Strip manhole and 48.0% (2.8%) of all genomes at facilities 2 and 3, respectively. During this time, it was estimated that visitors contributed more than 60% of the SARS-CoV-2 load to the sewershed serving the Las Vegas Strip and that Omicron prevalence among visitors was 40% to 60% on December 13 and 80% to 100% on December 20th. Conclusions and Relevance Wastewater surveillance is a valuable complement to clinical tools and can provide time-sensitive data for decision-makers and policy makers. This study represents a novel approach for quantifying the confounding effects of mobile populations on wastewater surveillance data, thereby allowing for modification of an existing WBE framework for estimating COVID-19 incidence in southern Nevada.
Kidney glycolysis serves as a mammalian phosphate sensor that maintains phosphate homeostasis
Authors: Wen Zhou, Petra Simic, Iris Y. Zhou, Peter Caravan, Xavier Vela Parada, Donghai Wen, Onica L. Washington, Maria Shvedova, Kerry A. Pierce, Clary B. Clish, Michael Mannstadt, Tatsuya Kobayashi, Marc N. Wein, Harald Jüppner, Eugene P. Rhee
Journal: Journal of Clinical Investigation (2023)

How phosphate levels are detected in mammals is unknown. The bone-derived hormone fibroblast growth factor 23 (FGF23) lowers blood phosphate levels by reducing kidney phosphate reabsorption and 1,25(OH)2D production, but phosphate does not directly stimulate bone FGF23 expression. Using PET scanning and LC-MS, we found that phosphate increases kidney-specific glycolysis and synthesis of glycerol-3-phosphate (G-3-P), which then circulates to bone to trigger FGF23 production. Further, we found that G-3-P dehydrogenase 1 (Gpd1), a cytosolic enzyme that synthesizes G-3-P and oxidizes NADH to NAD+, is required for phosphate-stimulated G-3-P and FGF23 production and prevention of hyperphosphatemia. In proximal tubule cells, we found that phosphate availability is substrate-limiting for glycolysis and G-3-P production and that increased glycolysis and Gpd1 activity are coupled through cytosolic NAD+ recycling. Finally, we show that the type II sodium-dependent phosphate cotransporter Npt2a, which is primarily expressed in the proximal tubule, conferred kidney specificity to phosphate-stimulated G-3-P production. Importantly, exogenous G-3-P stimulated FGF23 production when Npt2a or Gpd1 were absent, confirming that it was the key circulating factor downstream of glycolytic phosphate sensing in the kidney. Together, these findings place glycolysis at the nexus of mineral and energy metabolism and identify a kidney-bone feedback loop that controls phosphate homeostasis.
Updated results from the phase II study: Efficacy and safety of anlotinib plus sintilimab as second-line treatment for patients with advanced biliary tract cancers.
Authors: Shuiling Jin, Ruihua Zhao, Chuang Zhou, Qian Zhong, Xiaojian Zhang, Hong Zong
Journal: Journal of Clinical Oncology (2023)

577 Background: The incidence rate of biliary tract cancer (BTCs) is gradually increasing in china, while chemotherapy and immune checkpoint inhibitors monotherapy demonstrated limited efficacy for BTCs. New effective regimens are urgently needed. In this study, we explore anlotinib plus sintilimab as a chemo-free combination for second-line therapy. Previous results had been reported in 2021 ASCO GI (307 Poster Session). Updated results for longer follow-up and additional enrollment are presented here. Methods: BTC patients (pts) failed after the first-line treatment, aged 18-75 and an ECOG PS of 0-1 were recruited. Eligible pts received anlotinib (12mg, po, d1-14, q3w) and sintilimab (200mg, iv, d1, q3w) until disease progression, unacceptable toxicity or up to 2 years. The primary endpoint was Overall survival (OS). Secondary endpoints included Objective Response Rate, (ORR), Progression-Free Survival (PFS), Disease Control Rate (DCR) and safety. Results: At data cut-off date (Dec 30, 2021), a total of 29 pts were enrolled, of which 20 pts were available for efficacy assessment. The median treatment duration was 5.6 months (IQR: 2.5-10.0), and the median follow-up time was 12.5 months (IQR, 7.1-21.8). The median OS was 12.3 months (95% CI: 10.1-14.5).The median PFS was 6.5 months (95% CI: 4.2-8.8).The ORR was 30% (95% CI: 11.9%-54.3%) and DCR was 95% (95% CI: 75.1%-99.9%). Safety profile exhibited that the regimen was tolerable.The treatment-related adverse events (TRAEs) of any grade occurred in all patients (100%). The most common TRAEs were elevated GGT (75%), followed by hypertension (65%), elevated ALP (65%), elevated D-dimer (65%), elevated ALT (55%), anemia (50%), and elevated AST (50%). Grade 3 TRAEs occurred in 4 (20%) patients, including 2 (10%) hypertension, 1 (5%) elevated GGT, 1 (5%) elevated ALP, 1 (5%) elevated AST and 1 (5%) elevated ALT. No grade 4 or 5 TRAEs were observed. Conclusions: Anlotinib plus sintilimab demonstrated encouraging anti-tumor activity with a tolerable safety profile and deserve to be investigated in randomized trials for patients with advanced BTC. Clinical trial information: 1900022003 .
Phase I study of Minnelide and paclitaxel combination chemotherapy in refractory gastric cancer (GC).
Authors: Jeeyun Lee, Seung Tae Kim, Won Ki Kang, Ashok Saluja
Journal: Journal of Clinical Oncology (2023)

414 Background: Minnelide is a prodrug that rapidly releases the active compound triptolide when exposed to phosphatases in the bloodstream. Triptolide is a diterpene that has been shown to inhibit tumor cell proliferation and induce apoptosis in various cancer types. The anti-tumor effect of triptolide is the result of inhibition of heat shock protein (HSP) 70 expression. In GC Minnelide inhibits Sp1 to decrease HSP70 and induce cell death in preclinical data. Methods: This phase 1 trial was designed to determine the maximum tolerated dose (MTD) of Minnelide monotherapy and the MTD of Minnelide in combination with paclitaxel in refractory GC patients. There were 6 cohorts tested in this trial: cohort A: Minnelide 1 mg qd D1-21, q 28 days; cohort B: Minnelide 1.25 mg qd D1-21, q 28 days; cohort C: 1.5 mg qd D1-21, q 28 days; cohort D: Minnelide 0.25 mg D1-21 + weekly paclitaxel 60 mg/m 2 on D1, D8, D15; cohort E: Minnelide 0.5 mg qd D1-21+ weekly paclitaxel 80 mg/m 2 on D1, D8, D15; cohort F: Minnelide 0.75 mg qd D1-21+ weekly paclitaxel 80 mg/m 2 D1, D8, D15. Results: From Feb 2021 to Sep 2022, 23 GC patients were enrolled (cohort A – C, N=10; cohort D-F, N=12). All patients had metastatic disease at the time of study enrollment. 20 of 23 patients received the study treatment as &gt;= 3 rd -line (range, 2 – 6 th line). In all, 3 patients had HER2 positive GC and 10 patients had PDL1 + tumor. In the monotherapy cohorts, there were no DLTs observed, and the regimen was tolerated well. One patient achieved confirmed PR which lasted for 6 months. For the combination arm (cohort D-F), there were no DLTs observed. Of the 11 patients who were evaluable for treatment response, there were 1 PR, 5 SDs and 5 PDs. Two of five patients who achieved stable disease had durable stable disease for &gt; 6 months on study treatment. In the combination cohorts, the most common adverse events of any grade were neutropenia; however, there was no neutropenic fever or treatment related mortality. Conclusions: Minnelide in combination with weekly paclitaxel demonstrated promising anti-tumor activity with durable responses in refractory AGC. Clinical trial information: Underreview .
RSPO3 Furin domain-conjugated liposomes for selective drug delivery to LGR5-high cells
Authors: Peter van Kerkhof, Tomica Kralj, Francesca Spanevello, Louis van Bloois, Ingrid Jordens, Jelte van der Vaart, Cara Jamieson, Alessandra Merenda, Enrico Mastrobattista, Madelon M. Maurice
Journal: Journal of Controlled Release (2023)

The transmembrane receptor LGR5 potentiates Wnt/β-catenin signaling by binding both secreted R-spondin (RSPOs) and the Wnt tumor suppressors RNF43/ZNRF3, directing clearance of RNF43/ZNRF3 from the cell surface. Besides being widely used as a stem cell marker in various tissues, LGR5 is overexpressed in many types of malignancies, including colorectal cancer. Its expression characterizes a subpopulation of cancer cells that play a crucial role in tumor initiation, progression and cancer relapse, known as cancer stem cells (CSCs). For this reason, ongoing efforts are aimed at eradicating LGR5-positive CSCs. Here, we engineered liposomes decorated with different RSPO proteins to specifically detect and target LGR5-positive cells. Using fluorescence-loaded liposomes, we show that conjugation of full-length RSPO1 to the liposomal surface mediates aspecific, LGR5-independent cellular uptake, largely mediated by heparan sulfate proteoglycan binding. By contrast, liposomes decorated only with the Furin (FuFu) domains of RSPO3 are taken up by cells in a highly specific, LGR5-dependent manner. Moreover, encapsulating doxorubicin in FuFuRSPO3 liposomes allowed us to selectively inhibit the growth of LGR5-high cells. Thus, FuFuRSPO3-coated liposomes allow for the selective detection and ablation of LGR5-high cells, providing a potential drug delivery system for LGR5-targeted anti-cancer strategies.
Pharmacokinetics and RP2D analysis from ETCTN 10388: A phase I trial of triapine and lutetium Lu-177 dotatate in well-differentiated somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs).
Authors: Aman Chauhan, Susan M. Christner, Jan Hendrik Beumer, Charles Kunos, Aman Khurana, Riham El Khouli, Heidi Weiss, Donglin Yan, Heloisa P. Soares, Thorvardur Ragnar Halfdanarson, Daneng Li, William Edgar Carson, Mark B Evers, Percy Ivy, Elise C. Kohn, Larry Rubinstein, Susanne M. Arnold, Jill Kolesar, Lowell Brian Anthony, Bhavana Konda
Journal: Journal of Clinical Oncology (2023)

648 Background: Radiation is a potent inducer of DNA double-strand breaks, and ribonucleotide reductase (RNR) is the rate-limiting enzyme for conversion of ribonucleoside diphosphate to deoxyribonucleotide diphosphate, and thus repair of DNA in this setting. ETCTN 10388 evaluated safety of combination Lu-177 DOTATATE, a beta-emitting radionuclide in combination with triapine, a ribonucleotide reductase (RNR) inhibitor. Methods: This investigator initiated, NCI sponsored, multicenter phase 1 trial, enrolled a total of 31 patients in the dose escalation [using the Bayesian optimal interval design (BOIN)] and dose expansion cohorts. Oral triapine was administered on days 1-14 and Lu-177 DOTATATE [200 mCi] intravenously on day 1 of every 56-day cycle. A total of 4 cycles were administered. All enrolled patients had blood samples collected for triapine pharmacokinetic (PK) analysis in EDTA tubes prior to and at 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h after oral administration during cycle 1. Results: Five patients were enrolled in triapine Dose Level 1 (100 mg/day), twenty-five to dose level two (150 mg/day), and one patient to dose level three (200 mg/day). PK data were available for 12 patients enrolled in the dose escalation cohort. The geometric mean (SD) AUC 0-inf was 1159 (1.22) µg/L•h for the 100mg dose level and 1862 (1.76) µg/L•h for the 150 mg dose level, suggesting that exposure increased with dose, and inter-patient variability was as expected for an oral agent. Triapine PK parameter values observed in this trial, were comparable to previous reports that used a previous formulation [ 1 ]. While exposure was similar, variability appeared smaller with the current oral formulation. Adverse events (AE) were assessed in all 31 patients per CTCAE 5.0. A total of one DLT in dose level 1, seven DLTs (Transient cytopenia; primarily neutropenia and rarely thrombocytopenia) in dose level 2, and one grade 5 DLT (Death probably from progressive cancer and carcinoid heart disease but possibly from trial drugs) in dose level 3 were observed. Detailed AE profile will be presented at the meeting. Conclusions: The RP2D of triapine is 150 mg QD on days 1-14 in combination with Lu-177 DOTATATE on day 1 of every 56-day cycle. Clinical trial information: 04234568 .
BXQ-350 may alleviate symptoms of chemotherapy- induced peripheral neuropathy via modulation of S1P.
Authors: Robert Wesolowski, Anne M. Noonan, Richard Charles Curry, John Charles Morris, Carolyn Muller, Vinay K. Puduvalli, Olivier Rixe, John L. Villano, Trisha Michel Wise-Draper, Emrullah Yilmaz, Gilles Tapolsky, Ray Takigiku
Journal: Journal of Clinical Oncology (2023)

93 Background: Chemotherapy Induced Peripheral Neuropathy (CIPN) is a debilitating side effect associated with many chemotherapeutic agents. It significantly impacts quality of life during treatment, causes lasting neuropathy, and may also shorten the treatment regimen, potentially impacting clinical benefit. The pathology of CIPN is still not completely understood, however, increasing evidence suggests sphingosine-1-phosphate (S1P) may be an important signaling molecule. Altered neuronal sphingolipid metabolism has been linked to neuropathic pain, evidenced by elevated plasma levels of S1P in patients receiving chemotherapy. Methods: BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that lowers systemic S1P. BXQ-350 was investigated in an adult Phase 1 dose-escalation safety study in heavily pretreated all-comer cancer patients with advanced solid malignancies ( NCT02859857 ). The primary objective was to determine the safety profile and potential clinical activity of BXQ-350 as monotherapy. Samples were collected to explore potential biomarkers. Results: BXQ-350 was safe and well tolerated. Clinical signs of activity were observed in 13 patients (~17.8% of evaluable patients) experiencing a clinical benefit (PR, SD) up to cycle 6 and beyond including: 4 CRC, 1 pancreatic, and 1 GIST patient. Two patients are still on study six years after enrollment, including 1 CRC. Interestingly, a pancreatic cancer patient with chronic CIPN at time of enrollment spontaneously reported a significant improvement of her neuropathic symptoms shortly after receiving BXQ-350. Investigation of potential improvements in patients with chronic CIPN at time of enrollment revealed that 4 out of 10 patients experienced an improvement of their symptoms that seemed to be associated with a decrease in S1P systemic levels following BXQ-350 administration. BXQ-350 was subsequently investigated in a murine oxaliplatin-CIPN preclinical model with results showing a dose-dependent prevention/resolution of CIPN correlating with decreasing systemic S1P levels. Conclusions: Results of this Phase 1 study in heavily pretreated patients shows that BXQ-350 was well tolerated and seems to generate a clinical benefit via modulation of S1P. There were preliminary signs that BXQ-350 may alleviate symptoms of CIPN in relation to decreasing S1P concentration. Additional studies are underway to better understand this novel mechanism of action. Clinical trial information: 02859857 .